Two of the interleukins, IL-2 and IL-15, are functionally redundant in stimulating T cell proliferation in vitro. However, their role in primary immune activation and immune homeostasis in vivo is much less clear. In vivo, IL-2 and IL-15 may have distinct functions and regulate distinct aspects of T cell activation. For example, IL-2 may prime activated T cells for apoptosis (Lenardo, Nature 353:858-861, 1991), while IL-15 may support cell survival (Dooms et al., J. Immunol. 161:2141-2150, 1998; Bulfone et al. Nature Medicine 3:1124-1128, 1997). IL-15 also appears to drive the proliferation of memory type CD8+ T cells in vivo while IL-2 limits their continued expansion (Ku et al., Science 288:675-678, 2000). In addition, the phenotype of IL-2 deficient mice is lymphoproliferative and autoimmune (Horak et al., Immunol. Rev. 148:35-44, 1995), whereas IL-15 deficient mice are somewhat lymphopenic and unable to mount a primary response to viral challenge (Kennedy et al., J. Exp. Med. 191:771-780, 2000; Lodolce et al., Immunity 9:669-676, 1998). The molecular basis for this striking dichotomy remains enigmatic.
The functional receptors for IL-2 and IL-15 consist of a private α chain, which defines the binding specificity for IL-2 or IL-15, and shared IL-2 receptor β and γ chains. The γ chain is also a critical signaling component of the IL-4, IL-7, and IL-9 receptors (Sugamura et al., Ann. Rev. Immunol. 14:179-205, 1996). In the lymphoid compartment, these receptor subunits can be expressed individually or in various combinations resulting in the formation of receptors with different affinities and/or with distinct signaling capabilities (Sugamura et al., supra). For example, the β chain can associate with either the α chain or the γ chain to form dimeric structures, or with both the α and γ chains to form trimeric structures. Similarly, the γ chain can interact with the β chain and, through the β chain, with the α chain of either the IL-2 receptor or the IL-15 receptor. The IL-15 receptor α chain alone, in contrast to the IL-2 receptor α chain, can bind to IL-15 with a remarkably high affinity (Giri et al., EMBO J. 14:3654-3663, 1995). However, similar to IL-2 receptor α chain, this interaction is not believed to trigger signaling events. Thus, trimerization of α, β, and γ chain subunits is essential for the functional integrity of high affinity receptors for both IL-2 and IL-15.
In vitro studies have shown that activated T cells can express both IL-2 receptor α chain and IL-15 receptor α chain (Chae et al., J. Immunol. 157:2813-2819, 1996) and the β and γ chains are constitutively expressed by activated T cells (Ishii et al., Int. Immunol. 6:1273-1277, 1994). Furthermore, both IL-2 and IL-15 are readily detected during immune activation in vivo (Li et al., J. Immunol. 161:890-896, 1998). Thus, it is unclear how activated T cells distinguish between IL-2, IL-15, and other γ chain dependent cytokines in vivo.